Coronavirus Disease 2019 (COVID-19) Workup

Updated: Aug 03, 2020
  • Author: David J Cennimo, MD, FAAP, FACP, AAHIVS; Chief Editor: Michael Stuart Bronze, MD  more...
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Workup

Approach Considerations

Currently, diagnostic testing for SARS-CoV-2 infection can be conducted by the CDC, state public health laboratories, hospitals using their own developed and validated tests, and some commercial reference laboratories. [117]

State health departments with a patient under investigation (PUI) should contact CDC’s Emergency Operations Center (EOC) at 770-488-7100 for assistance with collection, storage, and shipment of clinical specimens for diagnostic testing. Specimens from the upper respiratory tract, lower respiratory tract, and serum should be collected to optimize the likelihood of detection. [95]

The FDA now recommends that nasal swabs that access just the front of the nose be used in symptomatic patients, allowing for (1) a more comfortable and simplified collection method and (2) self-collection at collection sites. [118]

Please see CDC Interim Guidance on Coronavirus Disease 2019 (COVID-19) for testing recommendations by the CDC.

The Infectious Diseases Society of America (IDSA) has also issued testing recommendations in terms of tier-based priority groups. [119]

According to the IDSA, the following patients should be considered highest priority for testing:

  • Patients who are critically ill or who have unexplained viral pneumonia or respiratory failure
  • Individuals with fever or signs/symptoms of lower respiratory tract illness who have had close contact with an individual with laboratory-confirmed COVID-19 within 14 days of symptom onset
  • Individuals with fever or signs/symptoms of lower respiratory tract illness who have traveled within 14 days of symptom onset to areas where sustained community transmission has been reported
  • Persons with fever or signs/symptoms of lower respiratory tract illness who are immunosuppressed, are older, or have underlying chronic health issues
  • Persons with fever or signs/symptoms of lower respiratory tract illness who are critical for the pandemic response, including healthcare workers, public health officials, and other essential leaders

Patients considered for second-priority testing include symptomatic residents of long-term care and hospitalized patients not in the ICU.

Patients considered for third-priority testing include those being treated in outpatient settings who meet criteria for influenza testing, including persons with certain comorbidities (eg, diabetes, COPD, CHF); pregnant women; and symptomatic pediatric patients with additional risk factors.

Finally, individuals considered for fourth-priority testing include persons who are undergoing monitoring for data collection and epidemiologic studies by health authorities.

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Laboratory Studies

Diagnostic Laboratory Studies

Polymerase chain reaction

The CDC has developed a diagnostic test for detection of the virus and received special Emergency Use Authorization (EUA) from the FDA on February 4, 2020, for its use. [120] The test is a real-time reverse transcription–polymerase chain reaction (rRT-PCR) assay that can be used to diagnose the virus in respiratory and serum samples from clinical specimens. [10]

Although the CDC rRT-PCR test was found to have performance issues related to manufacture of one of the reagents, the CDC has since developed an updated protocol that excludes the need for the third (problematic) component of the test without affecting accuracy. The test kits are now being shipped to US state and local public health laboratories that the CDC has determined to be qualified. [10]

On April 13, 2020, the FDA granted EUA for a saliva-based COVID-19 test, which can be used to test patients’ self-collected saliva rather than swabs collected by healthcare personnel, potentially limiting exposure and increasing the capacity for testing. [121]

Of note, commercially available molecular tests for other respiratory viruses (even those detecting endemic coronaviruses) have not demonstrated the ability to detect SARS-CoV-2. Australian scientists have successfully grown the virus in cultures. [122]

A Chinese study reported that positive rates varied by sample type tested. In 205 patients with confirmed COVID-19 among 3 hospitals, pharyngeal swabs were collected 1-3 days after admission. Other types of samples were also collected throughout illness—sputum, blood, urine, feces, nasal swabs, and bronchial brush or bronchoalveolar lavage (BAL) fluid. Samples were tested with RT-PCR. Of 1070 total samples tested, types with the highest rates of positive results included BAL fluid (14/15; 93%), sputum (75/104; 72%), nasal swabs (5/8; 63%), brush biopsy (6/13; 46%), pharyngeal swabs (126/398; 32%), feces (44/153; 29%), blood (3/307; 1%), and urine (0/72; 0%). Nasal swabs were found to contain the most virus. [123]

Upper respiratory tract specimens have been reported to contain a smaller viral load than lower respiratory tract specimens do. If PCR tests are negative for SARS-CoV-2 using upper respiratory tract specimens despite persistent clinical suspicion, the WHO recommends retesting using lower respiratory tract specimens. [124, 123]

Viral dynamics

Xiao et al studied the prolonged positivity of PCR results beyond the acute phase of infection in 56 patients with confirmed mild or moderate COVID-19 (none had been admitted to the ICU). SARS-CoV-2 RT-PCR testing was performed in each patient an average of 5 times (299 total tests administered). They found the highest rate of positivity at week one (100%), followed by 89.3% at week 2, 66.1% at week 3, 32.1% at week 4, 5.4% at week 5, and 0% at week 6. They also found that prolonged viral shedding occurred more often in older patients and in persons with comorbidities such as diabetes. [125] These findings may have implications in terms of “relapsed” infections and positive PCR results following negative ones. [126, 127]

The diagnostic value of repeated testing was illustrated in a study from Singapore in which 70 patients underwent SARS-CoV-2 PCR testing. Sixty-two patients tested positive for SARS-CoV-2 using the first clinical specimen collected (nasopharyngeal swab in all cases). A second test was administered 24 hours after the first test, yielding positive results in 5 patients whose initial results were negative. The three remaining patients tested positive after more than two tests. [128]

RT-PCR tests positive for SARS-CoV-2 after apparently resolved COVID-19 (two negative PCR results consecutively, along with clinical improvement) have been reported. Various theories for these “re-positive” results have been posited, including inactivated viral RNA being detected or viral reactivation. Nonetheless, positive results following consecutive negative ones occurred after a relatively short interval, probably do not indicate reinfection, may not reflect infectious SARS-CoV-2, and were not accompanied by worsening symptoms. In a Korean study, all confirmatory viral cultures performed (108) were negative for SARS-CoV-2 in patients in whom PCR results were “re-positive,” and contact tracing revealed no new COVID-19 cases linked to these patients after initial resolution. [129, 130, 131]

Please see CDC Interim Guidance on Coronavirus Disease 2019 (COVID-19) for additional testing recommendations by the CDC.

Antibody testing

Cheng et al reviewed data on serodiagnostics and advised that, as of June 2020, molecular testing is hampered by limited testing capacity and imperfect sensitivity and that antibody testing may be able to aid specific diagnostic scenarios but should not be used for diagnosing acute COVID-19. [132]

The FDA has issued emergency use authorization for a qualitative immunoglobulin M (IgM)/immunoglobulin G (IgG) antibody tests for SARS-CoV-2 using serum, plasma (EDTA or citrate), or venipuncture whole blood. IgM antibodies generally become detectable several days after initial infection, while IgG antibodies can be detected later. [133]

Recently, the FDA tightened requirements for companies that develop COVID-19 antibody tests in an effort to combat fraud and to better regulate the spate of tests that have come to market. The new approach requires all commercial manufacturers to submit EUA requests with validation data within 10 business days from the date they notified the FDA of their validation testing or from the date of the May 4 policy, whichever is later. A list of serology tests granted EUA from the FDA, along with their reported sensitivity and specificity rates, can be found at the FDA’s EUA Authorized Serology Test Performance page. [134, 135]

In a preprint study, Wu F et al analyzed plasma from 175 patients with COVID-19 in recovery who had experienced mild symptoms. They found that titers of neutralizing antibodies varied. Titers in 10 patients were below the level of detection. Higher levels of antibody correlated with older and middle age and higher CRP levels at admission but negatively correlated with lymphocyte count at admission. The authors raised concerns about the development of lasting immunity after infection. [136]

In a Chinese study of 66 patients with PCR-confirmed COVID-19 and another 24 patients with suspected but unconfirmed COVID-19, the seroconversion of specific IgM and IgG antibodies were observed as early as 4 days following symptom onset.

In the 66 patients with confirmed COVID-19, the sensitivity of IgM was found to be 77.3%; specificity, 100%; positive predictive value (PPV), 100%; negative predictive value (NPV), 80%; and consistency rate, 88.1%. For IgG, the sensitivity was found to be 83.3%; specificity, 95%; PPV, 94.8%; NPV, 83.8%; and consistency rate, 88.1%.

In the 24 patients with suspected but unconfirmed COVID-19, the sensitivity of IgM was 87.5%, specificity, 100%; PPV, 100%; NPV, 95.2%; and consistency rate, 96.4%. For IgG, the sensitivity was 70.8%; specificity, 96.6%; PPV, 85%; NPV, 89.1%; and consistency rate, 88.1%. [137]

Guo et al reported that IgM enzyme-linked immunoassay (ELISA) results were positive in 93% of patients with suspected COVID-19 (characteristic radiographic, clinical, and epidemiologic features) despite negative PCR results and despite negative results on plasma specimens tested before the COVID-19 outbreak. [138]

Viral culture

In patients with suspected COVID-19, virus isolation in cell culture or initial characterization of viral agents recovered in cultures of specimens is not recommended for biosafety reasons. [95]

Laboratory findings in patients with COVID-19

Leukopenia, leukocytosis, and lymphopenia were common among early cases. [34, 94]

Lactate dehydrogenase and ferritin levels are commonly elevated. [94]

Wu et al reported that, among 200 patients with COVID-19 who were hospitalized, older age, neutrophilia, and elevated lactate dehydrogenase and D-dimer levels increased the risks of ARDS and death. [106]

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CT Scanning

Chest CT scanning in patients with COVID-19–associated pneumonia usually shows ground-glass opacification, possibly with consolidation. Some studies have reported that abnormalities on chest CT scans are usually bilateral, involve the lower lobes, and have a peripheral distribution. Pleural effusion, pleural thickening, and lymphadenopathy have also been reported, although with less frequency. [94, 139, 140]

Bai et al reported the following common chest CT scanning features among 201 patients with CT abnormalities and positive RT-PCR results for COVID-19: [141]

  • Peripheral distribution (80%)
  • Ground-glass opacity (91%)
  • Fine reticular opacity (56%)
  • Vascular thickening (59%)

Less-common features on chest CT scanning included the following: [141]

  • Central and peripheral distribution (14%)
  • Pleural effusion (4.1%)
  • Lymphadenopathy (2.7%)

The American College of Radiology (ACR) recommends against using CT scanning for screening or diagnosis but instead reserving it for management in hospitalized patients. [142]

At least two studies have reported on manifestations of infection in apparently asymptomatic individuals. Hu et al reported on 24 asymptomatic infected persons in whom chest CT scanning revealed ground-glass opacities/patchy shadowing in 50% of cases. [143] Wang et al reported on 55 patients with asymptomatic infection, two-thirds of whom had evidence of pneumonia as revealed by CT scanning. [144]

Progression of CT abnormalities

Mingzhi et al recommend high-resolution CT scanning and reported the following CT changes over time in patients with COVID-19 among 3 Chinese hospitals: [145]

  • Early phase: Multiple small patchy shadows and interstitial changes begin to emerge in a distribution beginning near the pleura or bronchi rather than the pulmonary parenchyma.
  • Progressive phase: The lesions enlarge and increase, evolving to multiple ground-glass opacities and infiltrating consolidation in both lungs.
  • Severe phase: Massive pulmonary consolidations occur, while pleural effusion is rare.
  • Dissipative phase: Ground-glass opacities and pulmonary consolidations are absorbed completely. The lesions begin evolving into fibrosis. [145]
Axial chest CT demonstrates patchy ground-glass op Axial chest CT demonstrates patchy ground-glass opacities with peripheral distribution.
Coronal reconstruction chest CT of the same patien Coronal reconstruction chest CT of the same patient above, showing patchy ground-glass opacities.
Axial chest CT shows bilateral patchy consolidatio Axial chest CT shows bilateral patchy consolidations (arrows), some with peripheral ground-glass opacity. Findings are in peripheral and subpleural distribution.
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Chest Radiography

In a retrospective study of patients in Hong Kong with COVID-19, common abnormalities on chest radiography, when present, included consolidation (30 of 64 patients; 47%) and ground-glass opacities (33%). Consolidation was commonly bilateral and of lower zone distribution. Pleural effusion was an uncommon finding. Severity on chest radiography peaked 10-12 days following system onset. [146]

Chest radiography may reveal pulmonary infiltrates. [147]

The heart is normal in size. There are diffuse, pa The heart is normal in size. There are diffuse, patchy opacities throughout both lungs, which may represent multifocal viral/bacterial pneumonia versus pulmonary edema. These opacities are particularly confluent along the periphery of the right lung. There is left midlung platelike atelectasis. Obscuration of the left costophrenic angle may represent consolidation versus a pleural effusion with atelectasis. There is no pneumothorax.
The heart is normal in size. There are bilateral h The heart is normal in size. There are bilateral hazy opacities, with lower lobe predominance. These findings are consistent with multifocal/viral pneumonia. No pleural effusion or pneumothorax are seen.
The heart is normal in size. Patchy opacities are The heart is normal in size. Patchy opacities are seen throughout the lung fields. Patchy areas of consolidation at the right lung base partially silhouettes the right diaphragm. There is no effusion or pneumothorax. Degenerative changes of the thoracic spine are noted.
The same patient as above 10 days later. The same patient as above 10 days later.
The trachea is in midline. The cardiomediastinal s The trachea is in midline. The cardiomediastinal silhouette is normal in size. There are diffuse hazy reticulonodular opacities in both lungs. Differential diagnoses include viral pneumonia, multifocal bacterial pneumonia or ARDS. There is no pleural effusion or pneumothorax.
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